Type 2 Diabetes

Thomas Higgins, MD
6/26/01

The epidemic of obesity has been paralleled by a corresponding rise in Type 2 diabetes because of the association of increasing insulin resistance with increasing fat, especially visceral or central fat. Of particular concern is that up to 50% of the new cases of childhood diabetes represent Type 2 diabetes in some population groups – especially in the Latino and African-American populations.

Type 2 diabetes is a heterogeneous and very complex disorder representing an interplay between insulin resistance and decreasing insulin secretion by the insulin producing (Beta) cells in the pancreas. In the United States, at least 80% of people with Type 2 diabetes have insulin resistance as a major component of their disease but some populations such as the Asian population may have decreasing insulin production as the major factor in their Type 2 diabetes.

Early on in an individual destined to develop Type 2 diabetes, insulin resistance is moderate & increases with increasing weight, increasing stress, decreasing activity, increasing age & with the development of stress or other illness. Similarly, the defect in insulin secretion worsens with time. The initial defect in insulin secretion involves the first phase insulin of release from the Beta cell. First phase insulin release normally is brisk & occurs within seconds after ingesting food. This is in contrast to the second phase of insulin release which is lower in amplitude but more prolonged after ingestion of food. It should be apparent that the initial rise in glucose in the patient with early Type 2 diabetes and in the patient who is destined to develop diabetes but in whom the diagnosis can not yet be made (impaired glucose tolerance), occurs after a meal and is related to the loss of first phase insulin release. The fasting and the glucose several hours after a meal both return to normal in these patients. As the insulin resistance worsens & the defect in insulin secretion progresses, the glucose no longer returns to normal between meals. As the glucose rises, the high blood sugar itself causes a paradoxical fall in insulin secretion, a phenomena called "glucose toxicity". The glucose toxicity effect is reversible with a lowering of the blood sugar. In addition to glucose toxicity, there is an actual loss of beta cells with lengthening duration of diabetes.

Just as Type 2 diabetes is complex and progressive, its treatment is also complex and progressive. There are several principals to keep in mind. Increasing weight, increasing stress, decreasing exercise & acute illnesses are associated with increased insulin resistance. The basis of all treatment, therefore, involves dietary & life style changes together with the treatment of stress & any acute illness. Along with dietary management, diet medications may play a role in some obese patients. On the other hand, 20% of people with Type 2 diabetes may not be significantly insulin resistant and the above modalities may be less effective. 

As the disorder progresses, diabetes mediations become necessary. In the last several years we have developed a wide variety of medications for Type 2 diabetes which work in different ways. By thinking of the way the illness progresses we may be able to target our treatment to the changing needs of the person with Type 2 diabetes. For instance, early in the course of the disorder, it is first phase insulin release that appears to be defective. The use of Humalog insulin prior to meals in these patients may be appropriate. Inhaled insulin is now in clinical trials & may also be effective in this situation. An alpha galactosidase inhibitor which slows the absorption of carbohydrate or a sulfonylurea which causes insulin release may be tried. A  new oral agent for diabetes, nateglinide (Starlix) which seems to restore first phase insulin release, may also be effective. Over time, the disorder progresses with increasing insulin resistance & decreasing insulin secretion. The insulin sensitizing agents like the biguanides & thiazolidinediones can be used to target the increasing insulin resistance. Insulin sensitizing agents may be appropriate early in the treatment in patients where insulin resistance is severe. Finally, the reduction of beta cells may reduce the effectiveness of the sulfonylureas which cause insulin release, in this situation, longer acting insulins may become necessary.

Reversal of the glucose toxicity effect noted above with good control of the diabetes may actually slow the progression of the overall defect in insulin secretion & eventual loss of beta cells although this has not been proven.

Elevated glucose in diabetes is associated with adverse affects on small blood vessels in the kidneys, eyes, and nerves. In addition, high glucose accelerates the incidence of heart attack, stroke & peripheral vascular disease. The insulin resistance seen in Type 2 diabetes further magnifies this latter effect by further increasing the incidence of hypertension & lipid problems. Therefore, treatment of patients with Type 2 diabetes frequently also involves the treatment of other co-morbid conditions.

In summary, Type 2 diabetes is a complex & progressive disorder. Treatment of Type 2 diabetes is also both complex and progressive. The treatment involves multiple modalities, frequently involves multiple medications and often requires treatment of associated illnesses. Furthermore, Type 2 diabetes is increasing in frequency and is occurring at a younger age requiring more aggressive treatment over a longer period of time. The occurrence of Type 2 diabetes in children is a special problem as some of the medications, especially the thiazolidinediones may be contraindicated in this age group.

The reader is referred to other articles in this series dealing with other aspects of diabetes including insulin, oral agents & home glucose monitoring.